The mammalian brain consists of a diversity of neural circuits which must be wired correctly during development for normal function. Studies of excitatory synapses in sensory systems suggest that synaptic activity plays an important role in fine-tuning circuit connectivity, especially during the early post-natal period (Hooks &Chen 2007). Comparing how activity shapes neural wiring across circuit types provides valuable insight into how circuits are organized and ultimately function. We propose to dissect how synaptic activity influences the wiring of the Basal Ganglia (BG), a collection of forebrain nuclei involved in motor behavior, memory and habit formation. The BG network the brain through long-distance inhibitory projection neurons. These projections are organized into a series of parallel pathways that split and segregate neural information (Romanelli et al 2005). The two major splits, called the direct and indirect pathway, exert opposite effects on BG output and are thought to operate in balance to achieve normal function (Albin et al 1989). The goal of this proposal is to determine how synaptic activity influences the development of pathway segregation and balance. Specifically, we will use the cells that give rise to the direct and indirect pathway as our model. Using this system, we will address two questions. First, how does synaptic activity affect the development of MSN anatomical connections? Second, how does synaptic activity contribute to the development of balanced pathway physiology? We will pursue these questions experimentally by using transgenic mice that allow genes necessary or sufficient for synaptic transmission to be deleted or introduced selectively into MSNs of each pathway. Several clinically important disorders arise from BG dysfunction. Neurodegenerative diseases, like Parkinson's and Huntington's disease, are thought to be related to imbalances in the direct and indirect pathway specifically (DeLong &Wichmann 2007;Romanelli et al 2005). The BG also have a known role in generating addictive behavior (Belin et al 2009) and a speculative role in cognitive disorders such as Schizophrenia (Romanelli et al 2005). Establishing which aspects of circuit function are altered in disease states depends critically on understanding how activity and genetic programs interact to organize the circuit during development. PUBLIC HEALTH RELEVANCE: The Basal Ganglia (BG) network the brain through a series of parallel inhibitory pathways that exert opposite effects on BG output and motor behavior. Devastating neurodegenerative diseases like Parkinson's and Huntington's Disease are thought to arise from imbalances in these pathways. Here we genetically dissect how synaptic activity contributes to pathway organization during development.